Sleep is a ubiquitous yet mysterious animal behavior. Mounting evidence points to a crucial role for normal sleep in health and disease. This may be especially true for children with neurodevelopmental disorders such as Tuberous Sclerosis Complex (TSC). TSC is a neurogenetic syndrome that results from mutations in either the Tsc1 or Tsc2 genes that cause epilepsy, intellectual disability, and autism. Sleep dysfunction is reported in 50-90% of children with TSC and adversely affects daytime behavior, seizure control, metabolic homeostasis and psychological well- being. Treatment of sleep disorders in TSC and other neurodevelopmental syndromes has been limited by a fundamental lack of understanding of the mechanistic underpinnings of sleep dysfunction in these conditions. The proteins encoded by Tsc1 and Tsc2 inhibit the function of the mammalian target of rapamycin (mTOR), a conserved and critical integrator of nutrient status and anabolism in all cells. Dr. Lipton has used mouse models for TSC to establish a mechanistic link between the causes of TSC and the essential circadian clock protein BMAL1. These findings lead to the hypothesis that the Tsc/mTOR pathway is critical to the function of the central timekeeping mechanism in the brain, the suprachiasmatic nucleus of the hypothalamus (SCN). To test this hypothesis, the current mentored training plan has the following aims: (1) Determine the necessity and sufficiency of Tsc/mTOR signaling in the brain's central timekeeper, the suprachiasmatic nucleus (SCN); (2) Demonstrate the physiological requirement for Tsc/mTOR/S6K1-mediated phosphorylation of the crucial clock protein BMAL1 in vivo; (3) Determine the roles of TSC1/2 in sleep maintenance and homeostasis. These studies will establish the molecular role of the Tsc/mTOR pathway in the regulation of sleep and circadian rhythms. These studies will be carried at Children's Hospital Boston and Beth-Israel Deaconess Medical Center within the auspices of Harvard Medical School, under the dual mentorship of Dr. Clifford Saper, a renowned sleep scientist and neuroanatomist, and Dr. Mustafa Sahin, a child neurologist and pioneer in the understanding of the neurological basis for TSC. The Harvard Division of Sleep Medicine under the direction of Dr. Charles Czeisler provides a fertile environment for multi-disciplinary, cross-institutional academic training in sleep science and medicine at the highest level. Dr. Lipton is a child neurologist and sleep specialist with the career goal of becoming an independent physician-scientist committed to understanding the role of sleep and circadian rhythms in neurodevelopmental disorders. This mentored award will provide Dr. Lipton the structured training experience in experimental design and practice, didactics, and data analysis that will greatly facilitate the transition to a career as an independent physician-scientist. PUBLIC HEALTH RELEVANCE: Project Narrative Sleep has emerged as a critical variable in human health. Sleep dysfunction adversely affects daytime behavior, seizure control, and metabolic parameters and is therefore of particular importance to children with neurodevelopmental disorders. This proposal investigates the biological mechanisms of sleep and circadian dysfunction in mouse models of the neurodevelopmental disorder Tuberous Sclerosis Complex. The goal of this work is to identify rational therapeutic targets that would ameliorate sleep dysfunction that accompany disorders of the developing brain and to fundamental mechanisms that regulate sleep and circadian rhythms.